Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GBA1
SNOMEDCT: 12246008, 5963005, 62201009, 870313002;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38) : 1:155,234,452-155,244,627 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | {Lewy body dementia, susceptibility to} | 127750 | Autosomal dominant | 3 |
| {Parkinson disease, late-onset, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 | |
| Gaucher disease, perinatal lethal | 608013 | Autosomal recessive | 3 | |
| Gaucher disease, type I | 230800 | Autosomal recessive | 3 | |
| Gaucher disease, type II | 230900 | Autosomal recessive | 3 | |
| Gaucher disease, type III | 231000 | Autosomal recessive | 3 | |
| Gaucher disease, type IIIC | 231005 | Autosomal recessive | 3 |
Acid beta-glucocerebrosidase, also known as beta-glucosidase (GBA; EC 3.2.1.45), is a lysosomal enzyme that catalyzes the breakdown of the glycolipid glucosylceramide (GlcCer) to ceramide and glucose (Beutler, 1992).
Sorge et al. (1985) isolated and characterized a cDNA clone corresponding to the human beta-glucosidase gene from a human cDNA library. Using the ATG at positions 154-156 as the correct initiator codon, the deduced protein is 515 amino acids long and contains a 19-amino acid signal sequence. The mature 496-residue protein has a calculated molecular mass of 55.4 kD. The cDNA directed the synthesis of functional glucocerebrosidase when expressed in mammalian cells.
Tsuji et al. (1986) isolated GBA cDNA clones from a human hepatoma cDNA library. The deduced 516-residue protein has a calculated molecular mass of 57 kD.
Sorge et al. (1987) demonstrated that human GBA cDNA contains 2 potential ATG start codons, with the upstream ATG resulting in a protein with a 39-amino acid signal peptide and the downstream ATG resulting in a protein with a 19-amino acid signal peptide. The corresponding signal peptides differed in their hydrophobicity. Either ATG could function to produce active enzyme in cultured fibroblasts. Functional enzyme activity from either translation products was found predominantly in lysosomes.
Reiner et al. (1988) isolated 2 different genomic clones encoding human GBA from a fetal liver library. These clones represented 2 glucocerebrosidase genes, which the authors designated 6-1 and 10-2. The second gene is a putative pseudogene (see below). Both genes had identifiable promoter regions, but the promoter of gene 6-1 was much more efficient than that for gene 10-2 in a chloramphenicol acetyltransferase assay. Reiner et al. (1988) stated that both genes appear to be mapped at the same locus (Choudary et al., 1986).
Horowitz et al. (1989) identified 2 GBA mRNA species: a major 2.6-kb transcript and a minor 2.2-kb transcript.
O'Neill et al. (1989) found that the human and mouse GBA amino acid sequences share 86% identity. All 5 amino acids known to be essential for normal enzymatic activity are conserved between mouse and man. Only 1 ATG translation initiation signal was present in the mouse sequence, whereas 2 have been reported in the human sequence.
Pseudogene
Horowitz et al. (1989) sequenced a GBA pseudogene, which is 96% homologous to the functional gene. Compared to the functional gene, the pseudogene has large deletions within several introns, representing Alu sequences flanked by direct repeats, as well as base pair changes scattered throughout the gene. Reiner and Horowitz (1988) found that the promoter of the glucocerebrosidase pseudogene has demonstrable activity when attached to a reporter gene. They commented that mutations in the rest of the gene must render the mRNA vulnerable to breakdown or other functional abnormality such that no enzyme is synthesized.
By studies of RNA from lymphoblasts and fibroblasts from patients with Gaucher disease (see 230800) and normal subjects, Sorge et al. (1990) found that the pseudogene was consistently transcribed and that in some cases the level of transcription seemed to be approximately equal to that of the functional gene. The mouse genome did not appear to contain the pseudogene.
Tayebi et al. (1996) reported a method to distinguish the glucocerebrosidase gene from the pseudogene, which is 2 kb shorter than the expressed gene. The technique involved the use of long-template PCR and PCR primers to simultaneously generate a 5.6-kb fragment from the functional glucocerebrosidase gene and a 3.9-kb fragment from the pseudogene. The PCR products were then individually purified and used in subsequent experiments for mutation detection.
Horowitz et al. (1989) determined that the GBA gene contains 11 exons.
Shafit-Zagardo et al. (1981) assigned the GBA gene to chromosome 1p11-qter. Devine et al. (1982) narrowed the assignment to 1q42-qter. By study of hamster-human somatic cell hybrids, Barneveld et al. (1983) assigned GBA to 1q21-q31, which was consistent with the studies of Shafit-Zagardo et al. (1981) but not with those of Devine et al. (1982). Three studies suggested localization of the GBA gene in distal 1q31 or proximal subband 1q32.1 (Philip et al., 1985). By somatic cell hybridization and in situ hybridization, Ginns et al. (1985) placed GBA at 1q21.
Cormand et al. (1997) used an intragenic polymorphism of the GBA gene (6144A-G) to localize GBA in relation to markers in the Genethon human linkage map and to a 3.2-cM interval at chromosome 1q21. No recombination was found between 6 markers and the GBA gene. Three of the markers, D1S2777, D1S303, and D1S2140, are present in YAC clone 887h8 which also contains the GBA gene and the PKLR gene (609712). Mateu et al. (2002) found complete linkage disequilibrium in the PKLR-GBA region over 70 kb in a set of worldwide populations. Variation at PKLR-GBA was also tightly linked to that at the GBA pseudogene. Thus, a 90-kb linkage disequilibrium block was observed, which points to a low recombination rate in this region.
By linkage studies of interspecific backcrosses of Mus spretus and Mus musculus domesticus, Seldin (1989) demonstrated that the Gba gene is located on mouse chromosome 3. O'Neill et al. (1989) pointed out that although the NGFB (162030) and GBA loci are syntenic in both mouse and the human (they are about 7.6 cM apart on mouse chromosome 3), they represent a conserved segment that spans the centromere in man.
Pseudogene
The GBA pseudogene is located approximately 16 kb downstream from GBA (Sorge et al., 1990).
Zimran et al. (1989) identified a new mutation which represented crossing-over between the GBA gene and the pseudogene, resulting in a fusion gene designated 'XOVR.' Zimran et al. (1990) reported that this 'Lepore-like' glucocerebrosidase fusion gene consisted of the 5-prime end of the functional gene and the 3-prime end of the pseudogene. The location of a pseudogene near the functional gene for GBA on chromosome 1q may be the basis of disease-producing changes in the functional gene through gene conversion, similar to what occurs with the CYP21 gene (613815) on 6p (Horowitz, 1990).
Reczek et al. (2007) found that LIMP2 (SCARB2; 602257) bound beta-GC, but not alpha-galactosidase (GLA; 300644) or alpha-glucosidase (GAA; 606800). Beta-GC and LIMP2 interacted in the endoplasmic reticulum, and both proteins traversed the Golgi and endocytic compartments together en route to lysosomes. In vitro, low pH attenuated binding between the 2 proteins, suggesting that acidic lysosomal pH facilitates dissociation of beta-GC from LIMP2. Cross-linking experiments with transfected COS cells suggested that the beta-GC-LIMP2 complex is about 250 kD in size, consistent with a 2:2 beta-GC:LIMP2 stoichiometry. Mutation analysis revealed that a coiled-coil motif within the luminal domain of LIMP2 was required for beta-GC binding. Knockdown of LIMP2 in HeLa cells via small interfering RNA significantly reduced lysosomal beta-GC content and resulted in mistargeting of beta-GC for secretion. Limp2 knockout in mice significantly reduced beta-GC content in liver and kidney, but had no effect on beta-GC mRNA. Limp2 -/- mice, but not wildtype mice, showed elevated serum beta-GC and increased GlcCer content in liver and lung, but not in kidney, spleen, and brain. Limp2 -/- mice did not show a robust Gaucher-like phenotype. Reczek et al. (2007) concluded that LIMP2 functions as a mannose-6-phosphate-independent receptor for lysosomal targeting of beta-GC.
An association between Gaucher disease and Parkinson disease (PD; 168600; see MOLECULAR GENETICS) has been demonstrated by the concurrence of PD in some Gaucher disease patients and the identification of GBA mutations in some probands with sporadic PD. Ron et al. (2010) showed that mutant GBA variants associated with parkin (PARK2; 602544), and that wildtype parkin, but not its RING finger mutants, affected the stability of mutant GBA variants. Parkin also promoted the accumulation of mutant GBA in aggresome-like structures and was involved in lys48 (K48)-mediated polyubiquitination of GBA mutants, thus indicating its function as an E3 ligase. The authors suggested that involvement of parkin in the degradation of mutant GBA may explain the concurrence of Gaucher disease and PD.
Jovic et al. (2012) found that PI4KII-alpha (PI4K2A; 609763) and PI4KIII-beta (PI4KB; 602758), both of which synthesize phosphatidylinositol-4-phosphate (PtdIns4P), had distinct and sequential roles in the lysosomal delivery of beta-GC and LIMP2. Activity of PI4KIII-beta at the Golgi was required to drive exit of LIMP2 from the Golgi, whereas PI4KII-alpha at the trans-Golgi network regulated sorting of LIMP2 toward the late endosome/lysosome compartment. Knockdown or inhibition of PI3KIII-beta led to accumulation of LIMP2 at the Golgi compartment, and knockdown of either LIMP2 or PI4KII-alpha increased beta-GC secretion. Mutations in PI4KII-alpha that disrupted its association with AP3 (see AP3B1, 603401) disrupted lysosomal LIMP2 targeting.
By combining genetic perturbation of sphingolipid metabolism with quantification of TLR (see 601194) signaling steps and mass spectrometry-based lipidomics in mouse cells, Koberlin et al. (2015) uncovered a circular network of coregulated sphingolipids and glycerophospholipids. Quantitative lipidomics on fibroblasts from patients with mutations in GBA, GALC (606890), ASAH1 (613468), or LYST (606897) revealed conservation of the circular organization of lipid coregulation across species, cell types, and genetic perturbations. The functional annotation accurately predicted TLR-mediated inflammatory responses, in terms of changes in lipid abundance and lipid species, in patient cells.
Panicker et al. (2018) found that GBA1 deficiency did not appear to interfere with the ability of induced pluripotent stem cells (iPSCs) from Gaucher disease (GD; see 230800) patients to differentiate efficiently to mesenchymal stem cells (MSCs), but that it did interfere with differentiation from MSCs to osteoblasts and osteoblast bone-forming ability. GD iPSC osteoblasts had defective Wnt/beta-catenin signaling by mutant GBA1, which likely contributed to the defect in GD osteoblast differentiation. GD osteoblast differentiation could be restored by treatment with a potent inhibitor of GSK3-beta (605004). Assessment of the integrity of the lysosomal compartment in GD osteoblasts showed that mutant GBA1 had deleterious effects on the osteoblast lysosomal compartment, as Ca(2+)-dependent exocytosis, a lysosomal function critically required for bone matrix deposition, was significantly impaired. Furthermore, the lysosomal compartment in GD iPSC osteoblasts had defects in plasma membrane repair, another lysosome-dependent function important for osteoblast survival.
The numbering system used for some of the mutations in the MOLECULAR GENETICS and ALLELIC VARIANTS sections in this entry is based on the mature GBA protein and does not include the 39-residue signal peptide.
Gaucher Disease, Types I, II, and III
Nearly 200 mutations in the GBA gene have been described in patients with Gaucher disease types I (GD1; 230800), II (GD2; 230900), and III (GD3; 231000) (Jmoudiak and Futerman, 2005).
Tsuji et al. (1987) identified a mutation in the GBA gene (L444P; 606463.0001) in patients with Gaucher disease types I, II, and III. Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The L444P substitution occurs naturally in the GBA pseudogene.
Latham et al. (1990) presented a useful diagram of 9 mutations in the GBA gene identified in patients with Gaucher disease. Four of the mutations (L444P; D409H; 606463.0006, A456P and V460V; 606463.0009) were known to be present also in the pseudogene.
Beutler (1993), Mistry and Cox (1993), Horowitz and Zimran (1994), Beutler et al. (1994), Beutler and Gelbart (1996), and Stone et al. (2000) provided updates on mutations in the GBA gene causing Gaucher disease.
In an analysis of 60 type I and type III Gaucher patients, Sidransky et al. (1994) found that the 5 most common Gaucher mutations, N370S (606463.0003), L444P, R463C (606463.0008), 84insG, (606463.0014) and IVS2+1G-A (606463.0015), were identified in patients with or without neurologic manifestations. The findings indicated that Gaucher patients sharing identical genotypes can exhibit considerable clinical heterogeneity.
Grace et al. (1997) identified 6 new pathogenic mutations in the GBA gene in 5 severely affected type I and type II Gaucher disease patients of non-Jewish descent.
Sidransky et al. (1996) described homozygosity for a triply mutant GBA allele (606463.0009) in 2 conceptuses from an Afghan family with perinatal lethal Gaucher disease (608013). The findings were comparable to those in the 'knockout' Gaucher mouse in which absence of enzyme was incompatible with long survival (Tybulewicz et al., 1992). In an infant with perinatal lethal Gaucher disease, Tayebi et al. (1997) identified homozygosity for a null mutation in the GBA gene (606463.0034). This case confirmed the essential role of GBA in human development.
Germain et al. (1998) described an exhaustive screening strategy, involving fluorescence-assisted mismatch analysis using universal primers, and succeeded in identifying both Gaucher disease mutant alleles in all 25 patients studied. A total of 18 different mutations and a new Gaucher disease haplotype were detected.
In a patient with perinatal lethal Gaucher disease, Grace et al. (1999) identified 2 pathogenic alleles in the GBA gene. Stone et al. (2000) reported 6 children who presented at birth with collodion-type skin changes and hepatosplenomegaly and were found to be beta-glucocerebrosidase-deficient. All died shortly after birth or in the first year of life from respiratory insufficiency or progressive neurologic disease. Three of the cases were homozygous for GBA mutations (see 606463.0009 and 606463.0042) and the others were compound heterozygotes.
Park et al. (2002) noted that an E326K substitution had been identified in patients with all 3 types of Gaucher disease, but in each instance it was found on the same allele with another GBA mutation (see, e.g., 606463.0011). The authors identified the E326K allele in 1.3% of patients with Gaucher disease and in 0.9% of controls, indicating that it is a polymorphism. Montfort et al. (2004) performed functional analyses of 13 GBA mutant alleles identified in Gaucher disease patients. The mutations were expressed in Sf9 cells using a baculovirus expression system. The authors obtained results suggesting that the E326K mutation should be considered a 'modifier variant' rather than a neutral polymorphism, as previously suggested (Grace et al., 1999; Park et al., 2002).
Tayebi et al. (2003) studied DNA samples from 240 patients with Gaucher disease, using several complementary approaches to identify and characterize recombinant alleles. Among 480 alleles studied, 59 recombinant alleles were identified, including 34 gene conversions, 18 fusions, and 7 downstream duplications. At least 1 recombinant allele was present in 22% of the patients. In patients with Gaucher disease types I, II, and III, the authors found recombinant alleles with the following frequencies among alleles: 26 of 310, 18 of 74, and 15 of 96, respectively. Several patients carried 2 recombinations or mutations on the same allele. Generally, alleles resulting from nonreciprocal recombination (gene conversion) could be distinguished from those arising by reciprocal recombination (crossover and exchange), and the length of the converted sequence was determined. Homozygosity for a recombinant allele was associated with early lethality. Ten different sites of crossover and a shared pentamer motif sequence (CACCA) that could be a hotspot for recombination were identified.
Emre et al. (2008) analyzed the GBA gene in 57 unrelated Turkish patients with Gaucher disease and identified 103 mutant alleles (90.3%) carrying 11 different mutations, 3 of which were novel. The most frequent mutations included L444P (42%), N370S (30%), D409H (4.3%), and R463C (3.5%).
Late-Onset Parkinson Disease and Lewy Body Dementia
Goker-Alpan et al. (2004) reported 10 unrelated families with Gaucher disease in which obligate or confirmed carriers of GBA mutations developed Parkinson disease (see PD, 168600). In the family of a proband with Gaucher disease type III, the proband's father, paternal grandfather, and paternal great-aunt developed parkinsonism, and all were found to carry the mutant GBA allele that was found in the proband; 2 asymptomatic family members did not have the allele. Nine of 40 additional families with Gaucher disease had similar findings, but there was no correlation with specific GBA mutations. Most of the patients with parkinsonism developed neurocognitive changes. Goker-Alpan et al. (2004) suggested that heterozygosity for mutations in the GBA gene may be a risk factor for the development of parkinsonism.
Aharon-Peretz et al. (2004) reported an association between Parkinson disease and mutations in the GBA gene in Ashkenazi Jews by screening for 6 GBA mutations most common among this population. One or 2 mutant GBA alleles were identified in 31 (31.3%) of 99 Ashkenazi patients with idiopathic PD: 28 were heterozygous and 3 were homozygous for one of these mutations. Among 74 Ashkenazi patients with Alzheimer disease (AD; 104300), 3 (4.1%) were carriers of Gaucher disease and among 1,543 controls, 95 (6.2%) were carriers of Gaucher disease. Patients with PD had significantly greater odds of being carriers of Gaucher disease than did patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0). Among PD patients, those who were carriers of Gaucher disease were younger than those who were not carriers (mean age at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al. (2004) suggested that some GBA mutations are susceptibility factors for Parkinson disease.
Aharon-Peretz et al. (2005) observed no difference in overall clinical manifestations and age at disease onset between 40 Ashkenazi Jewish PD patients who carried GBA mutations and 108 Ashkenazi Jewish PD patients without GBA mutations.
Toft et al. (2006) did not find an association between PD and 2 common GBA mutations, L444P and N370S, among 311 Norwegian patients with Parkinson disease. Mutant GBA alleles were identified in 7 (2.3%) patients and 8 (1.7%) controls.
Goker-Alpan et al. (2006) identified heterozygous mutations in the GBA gene in 8 (23%) of 35 patients with dementia with Lewy bodies (DLB; 127750). Four of these individuals carried the N370S mutation. One of 28 patients with Parkinson disease also carried a heterozygous N370S mutation. The authors postulated that a mutant GBA enzyme may take on a different and unexpected role that may contribute to the development of synucleinopathies.
Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese.
Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish patients with PD carried a GBA mutation, compared to 4.2% of elderly and 6.35% of young controls. The proportion of severe GBA mutation carriers among patients was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and were associated with decreased age at PD onset. Gan-Or et al. (2008) concluded that genetic variance in the GBA gene is a risk factor for PD.
Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD.
Mata et al. (2008) identified heterozygosity for either the L444P or N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 DLB patients, and 2 (0.4%) of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.
Nichols et al. (2009) identified 9 different mutations in the GBA gene, including 5 previously reported variants, in 161 (12.2%) of 1,325 patients with Parkinson disease from 99 (17.5%) of 566 PD families, respectively. Statistical analysis indicated that presence of 1 of the 5 previously reported GBA mutation was associated with increased risk of PD as well as earlier age at disease onset compared to controls without a GBA mutation.
In a 16-center worldwide study comprising 5,691 PD patients (including 780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis), Sidransky et al. (2009) demonstrated a strong association between GBA mutations and Parkinson disease. Direct sequencing for only the L444P or N370S mutations identified either mutation in 15% of Ashkenazi patients and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either mutation was found in 3% of patients and less than 1% of controls. However, full gene sequencing identified GBA mutations in 7% of non-Ashkenazi patients. The odds ratio for any GBA mutation in patients compared to controls was 5.43 across all centers. Compared to PD patients without GBA mutations, patients with GBA mutations presented earlier with the disease, were more likely to have affected relatives, and were more more likely to have atypical manifestations, including cognitive defects. Sidransky et al. (2009) concluded that while GBA mutations are not likely a mendelian cause of PD, they do represent a susceptibility factor for development of the disorder.
Neumann et al. (2009) identified 14 different heterozygous mutations in the GBA gene in 33 (4.18%) of 790 British patients with Parkinson disease and in 3 (1.17%) of 257 controls. Three novel mutations (see, e.g., D443N; 606463.0048) were identified, and the most common mutations were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3 patients). Four (12%) patients had a family history of the disorder, whereas 29 (88%) had sporadic disease. The mean age at onset was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen (48.39%) of the patients with GBA mutations developed cognitive decline, including visual hallucinations. The male-to-female ratio of GBA carriers within the PD group was 5:2, which was significantly higher than that of the whole study group. Most patients responded initially to L-DOPA treatment. Neuropathologic examination of 17 GBA mutation carriers showed typical PD changes, with widespread and abundant alpha-synuclein pathology, and most also had neocortical Lewy body pathology. The prevalence of GBA mutations in British patients with sporadic PD was 3.7%, indicating that mutations in the GBA gene may be the most common risk factor for development of PD in this population. In an accompanying letter, Gan-Or et al. (2009) found that the data presented by Neumann et al. (2009) indicated that patients with mild GBA mutations had later age at onset (62.9 years vs 49.8 years) and lower frequency of cognitive symptoms (25% vs 55.6%) compared to patients with severe GBA mutations.
PD brains are characterized by accumulation of aggregated alpha-synuclein (SNCA; 163890), in addition to neurodegeneration. Mazzulli et al. (2011) found that postmortem brains of patients with GD and features of PD, as well as mouse models of GD, showed neuronal accumulation of SNCA. Functional loss of GCase and resultant GlcCer accumulation in cultured mouse cortical neurons and human neurons reprogrammed from induced pluripotent stem cells resulted in compromised lysosomal degradation of long-lived proteins, including SNCA. Elevated cellular GlcCer also promoted SNCA aggregation. SNCA accumulation in turn inhibited normal lysosomal GCase activity in neurons and PD brain. In apparently normal human cortical samples, SNCA protein content, particularly high molecular mass species, correlated inversely with GCase activity. Mazzulli et al. (2011) hypothesized that a positive-feedback loop between defective SNCA and/or GCase could lead to self-propagating neurodegeneration over time.
Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 years of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. The N370S mutation was not found in any of the Mexican individuals, suggesting a similarity to Asian populations in which the N370S mutation is almost nonexistent. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms.
Theophilus et al. (1989) confirmed the high frequency of the N370S mutation in Ashkenazi Jewish patients with type I Gaucher disease. Homozygotes were mildly affected older persons, and the mutant allele was not found in any patient with neuronopathic disease. Furthermore, they confirmed that the L444P mutation was the predominant allele in Gaucher disease type II and type III.
Koprivica et al. (2000) used several approaches, including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system, to genotype 128 patients with type I Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type III Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Four mutations (N370S, 84insG, IVS2+1G-A, and L444P) accounted for 93% of the mutant alleles in the Ashkenazi Jewish type I patients, but for only 49% of mutant alleles in the non-Jewish type I patients. Heterozygosity for N370S resulted in type I Gaucher disease, whereas homozygosity for L444P was associated with type III. Genotype L444P/recombinant allele resulted in type II Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease.
Homozygosity for the D409H mutation (606464.0006) has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with neuronopathic Gaucher disease and cardiovascular calcifications, a specific subtype known as 'Gaucher disease type IIIC' (231005) (Bohlega et al., 2000). These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher disease.
Ron and Horowitz (2005) tested glucocerebrosidase protein levels, N-glycans processing, and intracellular localization in skin fibroblasts derived from patients with Gaucher disease. Their results strongly suggested that mutant glucocerebrosidase variants presented variable levels of ER retention and underwent ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation was 1 of the factors that determined Gaucher disease severity.
In a review of the molecular genetics of Gaucher disease, Hruska et al. (2008) noted that most GBA mutations can be found in patients with various forms of the disorder. The phenotype is mainly determined by the combination of mutations on both alleles; thus the prediction of phenotype from genotypic data has limited utility. In addition, it has become increasingly difficult to categorize patients into 1 of the 3 classic types of Gaucher disease, indicating that the phenotypes fall into a continuum, with the major distinction being the presence and degree of neurologic function.
Beutler (1993) stated that the 2 most common mutations in the Ashkenazi Jewish population were N370S and 84insG, representing approximately 77% and 13% of mutant alleles, respectively. These 2 mutations, together with L444P, IVS2+1G-A, and V394L (606463.0005), account for 98% of the disease-causing alleles in this population. Each of these mutations was found in the context of a single haplotype, consistent with a founder effect.
Diaz et al. (2000) used short tandem repeat (STR) markers to map a 9.3-cM region containing the GBA locus and to genotype 261 Ashkenazi Jewish N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 Ashkenazi Jewish 84insG chromosomes. A highly conserved haplotype at 4 markers flanking GBA was observed on both the Ashkenazi chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to the 2 populations. The presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84insG chromosomes, which was unique to the Ashkenazi population. On the basis of linkage disequilibrium values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less linkage disequilibrium at the markers flanking the conserved haplotype than did the Ashkenazi N370S chromosomes. This finding was considered consistent with the presence of the N370S mutation in the non-Jewish European population before the founding of the Ashkenazi population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. (Coalescence time refers to the number of generations to the most recent common ancestor, MRCA.) The results of these studies were consistent with a significant bottleneck occurring in the Ashkenazi population during the first millennium, when the population became established.
A naturally occurring canine model of Gaucher disease was reported by van de Water et al. (1979) but was not propagated. Tybulewicz et al. (1992) produced a murine model by targeted disruption of the mouse Gba gene. A null allele was created in embryonic stem cells, and the genetically modified cells were used to establish a mouse strain carrying the mutation. Mice homozygous for the mutation had less than 4% of normal glucocerebrosidase activity, died within 24 hours of birth, and stored glucocerebroside in lysosomes of cells of the reticuloendothelial system.
To produce mice with point mutations that correspond to the clinical types of Gaucher disease, Liu et al. (1998) devised a highly efficient 1-step mutagenesis method, called the single insertion mutagenesis procedure (SIMP), to introduce human disease mutations into the mouse Gba gene. By use of SIMP, they generated mice carrying either the very severe triply mutant allele (606463.0009) that can cause type II disease or the less severe L444P mutation associated with type III disease. Mice homozygous for the triple mutation had little GBA enzyme activity and accumulated glucosylceramide in brain and liver. In contrast, the mice homozygous for the L444P mutation had higher levels of GBA activity and no detectable accumulation of glucosylceramide in brain and liver. Surprisingly, both point mutation mice died within 48 hours of birth, apparently of a compromised epidermal permeability barrier caused by defective glucosylceramide metabolism in the epidermis.
Enquist et al. (2007) generated transgenic mice with targeted disruption of the Gba gene, but low expression of the gene in skin to prevent early lethality. The mice showed a phenotype similar to the severe neuronopathic form of Gaucher disease, including rapid motor dysfunction, seizures, and hyperextension of the neck associated with severe neurodegeneration and apoptotic neuronal cell death. Some neurons had large vacuoles indicating neuronal lipid accumulation. A second mouse model with Gba deficiency restricted to neural and glial cell progenitors demonstrated a similar neuropathology as the first mouse model, but with a delayed onset and slower disease progression. These findings indicated that Gba deficiency within microglial cells of hematopoietic origin is not the primary determinant of the CNS pathology, but may influence disease progression. The findings also showed that normal hematopoietic-derived microglial cells could not rescue the neurodegenerative phenotype.
The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013).
Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation.
Gaucher Disease
Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene.
Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III.
Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation.
In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P.
Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease.
Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot.
Parkinson Disease
Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese.
Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD.
Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls.
Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms.
Lewy Body Dementia
Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.
In a patient with Gaucher disease type II (230900), Wigderson et al. (1989) identified compound heterozygosity for 2 mutations in the GBA gene: a 5976C-G transversion, resulting in a pro415-to-arg (P415R) substitution, and L444P (606463.0001).
Reczek et al. (2007) found that GBA with the P415R mutation was retained in the ER of transfected mouse embryonic fibroblasts. Overexpression of the GBA receptor, LIMP2 (SCARB2; 602257), did not rescue lysosomal targeting of GBA with the P415R mutation, suggesting that this mutation directly or indirectly interferes with interaction between GBA and LIMP2.
Gaucher Disease
The asn370-to-ser (N370S) substitution in exon 9 of the GBA gene has been reported as resulting from a 5841A-G transition (Latham et al., 1990) and from a 1226A-G transition (Tsuji et al., 1988), depending upon the reference sequence cited. It is the most common Gaucher disease allele in the Ashkenazi Jewish population and is only associated with the nonneuronopathic type I form of Gaucher disease (230800) (Zimran et al., 1989).
Tsuji et al. (1988) identified the N370S substitution in an Ashkenazi Jewish patient with type I Gaucher disease. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation occurs exclusively with the type I phenotype. None of 6 type II (230900) patients, 11 type III (231000) patients, or 12 normal controls had this allele. In contrast, 15 of 24 type I patients had 1 allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazi Jewish type I patients had only 1 allele with this mutation, suggesting allelic heterogeneity even in this population. One patient with type I disease was compound heterozygous for N370S and L444P (606463.0001).
Zimran et al. (1989) found that the N370S substitution was associated with a mild clinical phenotype compared to L444P. Eight of 22 patients homozygous for N370S were entirely symptom-free. In symptomatic patients, the clinical features of the N370S homozygotes were usually related to splenomegaly and thrombocytopenia.
Kolodny et al. (1989, 1990) studied an unusual Ashkenazi Jewish family with affected members in 3 successive generations. Both N370S and L444P segregated in the family; 4 affected individuals were homozygous for N370S mutation, while 3 others were compound heterozygotes for the 2 mutations. Clinical severity was more marked in compound heterozygotes than in homozygotes. Firon et al. (1990) found the N370S mutation in type I patients only.
Zimran et al. (1990) identified a 3931G-A polymorphism in intron 6 of the GBA gene, termed PvuII. Analysis of 54 unrelated Jewish Gaucher patients showed strong linkage disequilibrium between the negative polymorphism genotype and the common Jewish N370S mutation.
Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele.
Mistry et al. (1992) used the amplification refractory mutation system (ARMS) for direct detection of GBA mutations in Gaucher disease. PCR primers were designed to discriminate between mutant and wildtype alleles and to allow separation from products of the related pseudogene. The N370S mutation and a 2-bp insertion (84insGG; 606463.0014) were found exclusively in 5 patients of Ashkenazi Jewish descent.
Van Weely et al. (1993) studied the properties of control and N370S mutant GBA in vitro and in vivo. The results indicated that the intralysosomal pH in the intact cell has a critical influence on the activation state of N370S GBA and its ability to hydrolyze substrate. This phenomenon may partly explain the clinical heterogeneity in patients with Gaucher disease caused by the N370S mutation.
Walley et al. (1993) found that the N370S mutation accounted for 26% of Gaucher disease alleles among non-Jewish patients in the United Kingdom (total alleles = 54). They found a correlation between the presence of at least 1 N370S allele and mild disease. The L444P mutation accounted for 35% of the alleles and the remaining 39% were rare or undefined.
The N370S mutation and the 84insGG mutation reportedly account for approximately 70% and 10%, respectively, of mutations in the Jewish population. Ida et al. (1995) found neither mutation in 32 unrelated Japanese Gaucher patients, of whom 20 were type I, 6 were type II, and 6 were type III.
Cormand et al. (1998) found that N370S and L444P accounted for 66.1% of Gaucher disease alleles in Spain. Linkage disequilibrium was detected between these 2 mutations and an intragenic polymorphism, indicating that expansion of founder alleles occurred in both cases. Analysis of several microsatellite markers close to the GBA gene allowed them to establish a putative haplotype of the ancestral N370S chromosome.
Koprivica et al. (2000) found that homozygosity or heterozygosity for N370S resulted in type I Gaucher disease.
Dimitriou et al. (2010) determined that the frequency of the N370S allele is 0.0046 in the Greek population.
Parkinson Disease and Lewy Body Dementia
Mata et al. (2008) identified heterozygosity for the N370S mutation in 11 (1.5%) of 721 patients with Parkinson disease (PD; 168600), 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 2 (0.4%) of 554 control individuals. All individuals were of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.
Neumann et al. (2009) identified a heterozygous N370S mutation in 8 (1.01%) of 790 British patients with PD and in 1 (0.39%) of 257 controls.
The arg119-to-gln (R119Q) substitution in the GBA gene has been reported to result from a 3060G-A transition (Graves et al., 1988) and a 476G-A transition (Felderhoff-Mueser et al., 2004), depending upon the reference sequence cited. This mutation has also been referred to as ARG120GLN by others (Latham et al., 1990; Felderhoff-Mueser et al., 2004).
Graves et al. (1988) identified a heterozygous R119Q substitution in the GBA gene in 2 Ashkenazi Jewish cousins with Gaucher disease type I (230800).
In a premature infant with the perinatal lethal form of Gaucher disease (608013), Felderhoff-Mueser et al. (2004) identified compound heterozygosity for the R120Q mutation and an IVS10-1G-A substitution (606463.0046) in the GBA gene.
Theophilus et al. (1989) and Latham et al. (1990) identified a heterozygous 5912G-T transversion in the GBA gene, resulting in a val394-to-leu (V394L) substitution, in an Ashkenazi Jewish/Irish patient with Gaucher disease type III (231000) and an Ashkenazi Jewish patient with Gaucher disease type I (230800). The patient with type III disease was compound heterozygous for the V394L substitution on 1 allele and a complex substitution (606463.0009) and D409H (606463.0006) on the other allele. He developed psychomotor retardation and myoclonic seizures by age 5 years and died at 6 years. The patient with type I disease was compound heterozygous for V394L and N370S (606463.0003). Latham et al. (1990) suggested that the N370S allele protected the type I patient from the development of neuronopathic disease.
Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide.
The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992).
Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease.
Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease.
Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement.
Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications.
Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome.
Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.'
Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement.
Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013).
Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly.
In a Caucasian patient with type III Gaucher disease (231000), Theophilus et al. (1989) identified compound heterozygosity for 2 mutations in the GBA gene: a 5958A-T transversion in exon 9, resulting in an asp409-to-val (D409V) substitution, and L444P (606463.0001).
The ASP409VAL variant is annotated as ASP448VAL based on sequence NM_000157.3; see 606463.0006. The sequence includes the 39-residue signal peptide.
Gaucher Disease
In a non-Jewish patient with type I Gaucher disease (230800), Hong et al. (1990) identified a 1504C-T transition in exon 10 of the GBA gene, resulting in an arg463-to-cys (R463C) substitution.
By the amplification refractory mutation system, Mistry et al. (1992) identified the R463C mutation and the L444P mutation (606463.0001) in association with rapidly progressive disease and neurologic involvement in non-Jewish patients (see 230900).
Park et al. (2003) identified the R463C mutation in patients with type III Gaucher disease (231000).
Parkinson Disease
Neumann et al. (2009) identified a heterozygous R463C mutation in 3 (0.38%) of 790 British patients with Parkinson disease (PD; 168600) that was not found in 257 controls, suggesting that heterozygosity for the mutation increases susceptibility for development of PD.
In 3 non-Jewish patients with Gaucher disease type I (230800) and 1 non-Jewish patient with type II disease (230900), Hong et al. (1990) found a mutant allele containing 3 single-base substitutions in exon 10 of the GBA gene, resulting in L444P (606463.0001), ala456-to-pro (A456P), and val460-to-val (V460V) substitutions. This mutant allele was referred to as 'pseudopattern' because it has sequence identical to a small region of exon 10 in the pseudogene (Horowitz et al., 1989). At least one of the patients was a compound heterozygote; the other allele was N370S (606463.0003). The authors suggested either gene conversion or recombination as a possible mechanism.
Latham et al. (1990) independently found these 3 mutations on 1 allele in patients with types I, II, and III (231000) Gaucher disease. None was homozygous for the complex allele: all patients had it in compound heterozygosity with another pathogenic GBA mutation.
Sidransky et al. (1996) described homozygosity for this complex triply mutant allele in 2 conceptuses from an Afghan family with perinatal lethal Gaucher disease (608013). The first infant had severe hydrops fetalis with bilateral hydrothorax and fetal hypokinesia with multiple joint contractures. Other features included hepatosplenomegaly, pulmonary hypoplasia, muscular atrophy, dysmorphic facies, and ichthyosis-like changes of the skin. The infant died less than an hour after delivery. In the next pregnancy a prenatal diagnosis of Gaucher disease was made by enzyme assay on cultured amniocytes obtained at week 15. Neither hydrops nor joint contractures were found in the fetus aborted at 23 weeks' gestation. The complex mutant allele is thought to have arisen by gene conversion or a recombination event with the neighboring pseudogene. The findings are comparable to those in the 'knockout' Gaucher mouse in which absence of enzyme is incompatible with long survival (Sidransky et al., 1992; Tybulewicz et al., 1992). A presumed homozygote for this complex allele, behaving as a perinatal lethal, was reported by Strasberg et al. (1994) in a fetus of Macedonian/Ashkenazi Jewish parentage.
Stone et al. (2000) reported a male infant born to consanguineous Lebanese parents who was homozygous for this recombinant allele. Ultrasound scanning demonstrated reduced fetal movement, neck hyperextension, and hepatomegaly. He was born at 34 weeks' gestation and died shortly thereafter. Autopsy findings included thick collodion-like skin, ectropia, joint contractures, hepatosplenomegaly, and facial dysmorphism. Gaucher cells were seen in many tissues. The diagnosis of Gaucher disease was confirmed enzymatically.
In an 11-year-old, non-Jewish Caucasian girl with type I Gaucher disease (230800), Beutler and Gelbart (1990) identified a 764T-A transversion in the GBA gene, resulting in a phe216-to-tyr (F216Y) substitution. The patient was heterozygous for this mutation, which came from the father; the presumed abnormality in the other allele was not identified.
In 2 brothers with type I Gaucher disease (230800), Eyal et al. (1991) identified 3 point mutations in the GBA gene. One chromosome, inherited from the mother, had a 3119G-A transition resulting in an asp140-to-his (D140H) substitution, and a 5309G-A transition resulting in a glu326-to-lys (E326K) substitution. The other chromosome, inherited from the father, had a 3170A-C transversion resulting in a lys157-to-gln (K157Q; 606463.0012) substitution. All 3 mutations were inherited through 3 generations; the his140 and lys326 mutations were transmitted together. Although 1 brother had neurologic features, postmortem analysis did not detect Gaucher cells in the central nervous system, and Eyal et al. (1991) concluded that he had an additional separate neurologic disorder. The other brother had clinical features consistent with type I Gaucher disease.
By functional analysis studies of mutant GBA proteins, Montfort et al. (2004) obtained results suggesting that the E326K substitution alone could be considered a 'modifier variant' rather than a neutral polymorphism, as previously suggested (Grace et al., 1999; Park et al., 2002).
For discussion of the 3170A-C transversion in the GBA gene, resulting in a lys157-to-gln (K157Q) substitution, that was found in compound heterozygous state in 2 brothers with type I Gaucher disease (230800) by Eyal et al. (1991), see 606463.0011.
In a Japanese patient with type III Gaucher disease (231000), Kawame and Eto (1991) identified a heterozygous 3548T-A transition in exon 6 of the GBA gene, resulting in a phe213-to-ile (F213I) substitution. Two additional unrelated Japanese patients with type II Gaucher disease (230900) were also found to carry this mutation. F231I is normally found in the GBA pseudogene. The patients were compound heterozygous for F213I and L444P (606463.0001). In a patient with type I Gaucher disease (230800), He et al. (1992) found compound heterozygosity for 2 mutations in the GBA gene: P213I and P289L (606463.0016).
In Ashkenazi Jewish patients with type I Gaucher disease (230800), Beutler et al. (1991) identified a 1-bp insertion (84insG) of a second guanine at cDNA nucleotide 84; the mutation was referred to as the '84GG' mutation.
Beutler et al. (1993) found that 10 of 2,305 normal Ashkenazi Jewish individuals were heterozygous for the 84GG insertion mutation, yielding an allele frequency of 0.00217.
Ida et al. (1995) did not identify the 84GG mutation in 32 unrelated Japanese Gaucher patients, of whom 20 were type I, 6 were type II (230900), and 6 were type III (231000).
In a survey of 100 unrelated Jewish patients with type I Gaucher disease (230800), Beutler et al. (1992) found that 5 of the mutant GBA alleles resulted from a splice site mutation in intron 2 (IVS2DS+1G-A), resulting in skipping of exon 2. The phenotype was associated with earlier onset and more severe disease compared to the common N370S mutation (606463.0003).
He and Grabowski (1992) identified the IVS2DS+1G-A transition in a moderately affected 9-year-old Ashkenazi Jewish patient with type I Gaucher disease. The transition was found also at the corresponding exon/intron boundary of the highly homologous pseudogene. This splicing mutation accounted for about 3.4% of the Gaucher disease alleles in the Ashkenazi Jewish population.
Stone et al. (2000) identified compound heterozygosity for the IVS2DS+1G-A mutation and L444P (606463.0001) in 2 unrelated patients with type II Gaucher disease (230900).
In a patient with type I Gaucher disease (230800), He et al. (1992) found compound heterozygosity for 2 mutations in the GBA gene: a pro289-to-leu (P289L) and P213I (606463.0013) substitution. The latter mutation had previously been found in type III patients.
In a patient with type I Gaucher disease (230800), He et al. (1992) found compound heterozygosity for a thr323-to-ile (T323I) substitution and the R463C (606463.0008) mutation in the GBA gene.
In an infant with severe, lethal type II Gaucher disease (230900) and severely decreased glucocerebrosidase activity, Saranjam et al. (2013) identified compound heterozygosity for 2 mutations in the GBA gene: a c.1085C-T transition, resulting in a thr323-to-ile (T323I) substitution inherited from the unaffected father, and the common L444P mutation (606463.0001). However, the L444P mutation was not identified in several tissues from the mother, and her glucocerebrosidase activity was normal. The findings suggested that the L444P mutation occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot.
Saranjam et al. (2013) alternatively referred to this mutation as THR362ILE.
In a 6-year-old non-Jewish European patient with Gaucher disease type I (230800), Beutler et al. (1993) identified a 1-bp deletion (72delC; 1023delC in the genomic sequence) in the GBA gene. The nature of the other mutation was not determined. There were no neurologic findings. The mutation was suspected on the basis of SSCP analysis and confirmed by sequencing and by restriction endonuclease analysis. In this and the other 5 patients with 'new' mutations whom they described, Beutler et al. (1993) cited a severity score which varied in the group of patients from 2 to 15; the patient with the 1023delC mutation had a severity score of 5.
Beutler et al. (1993) identified homozygosity for a pro122-to-ser (P122S) mutation in a 3-year-old Native American patient with Gaucher disease type I (230800) of severity score 12 and no neurologic findings. The amino acid substitution was due to a 3065C-T transition (genomic DNA sequence) and abolished a KpnI restriction site.
In a Jewish patient with type I Gaucher disease (230800), Beutler et al. (1993) identified compound heterozygosity for 2 mutations in the GBA gene: a 751T-C transition (3545T-C in the genomic DNA), resulting in a tyr212-to-his (Y212H) substitution, and N370S (606463.0003).
In a non-Jewish European patient with type I Gaucher disease (230800), Beutler et al. (1993) identified compound heterozygosity for 2 mutations in the GBA gene: a 1549G-A transition (6628G-A in the genomic DNA) resulting in a gly478-to-ser (G478S) substitution, and N370S (606463.0003). The severity score was given as 15, the highest value in this particular series of reported cases. There were no neurologic symptoms.
In 4 unrelated patients, 3 Jewish and 1 non-Jewish European, with type I Gaucher disease (230800), Beutler et al. (1993) identified a heterozygous 1604G-A transition (6683 in the genomic DNA sequence) in the GBA gene, resulting in an arg496-to-his (R496H) substitution. Age at diagnosis varied from 16 to 27 years. None had neurologic findings. Severity score varied from 2 to 9. The other mutation in 3 of the patients was that referred to as 84GG (606463.0014); the fourth patient, Jewish, had the common N370S mutation (606463.0003).
In a non-Jewish European patient with type I Gaucher disease (230800), Beutler et al. (1993) identified a 55-bp deletion (nucleotides 1263-1317 in the cDNA; nucleotides 5879-5933 in genomic DNA) in the GBA gene. The mutation was in compound heterozygous combination with the N370S mutation (606463.0003). The severity score was given as 12.
Stone et al. (2000) reported a preterm female infant, born to nonconsanguineous Australian parents, with collodion skin, ectropia, hepatosplenomegaly, and thrombocytopenia (608013). She had a leucocyte glucocerebrosidase activity of 53 pmol/min/mg (normal, 600-3200). She was compound heterozygous for the 55-bp deletion and an R257E substitution (606463.0041).
By sequencing RT-PCR cDNAs from 5 unrelated Korean and 2 Taiwanese sibs with Gaucher disease type I (230800), Kim et al. (1996) identified 3 mutations in the GBA gene: V15L, G46E (606463.0025), and N188S (606463.0026). Each mutation resulted in a dysfunctional acid beta-glucosidase. The N188S allele was present in both the Korean and the Chinese populations, suggesting an ancient mutation. The G46E mutation was present in 2 unrelated Korean patients.
Kim et al. (1996) identified a gly46-to-glu (G46E) substitution in the GBA gene in 2 unrelated Korean patients with type I Gaucher disease (230800).
Kim et al. (1996) identified an asn188-to-ser (N188S) substitution in the GBA gene in both Korean and Chinese (Taiwanese) patients with type I Gaucher disease (230800), suggesting that this is an ancient mutation.
Park et al. (2003) identified a heterozygous N188S mutation in 4 unrelated adult patients with type III Gaucher disease and myoclonic epilepsy (231000). All were compound heterozygous for another pathogenic GBA mutation.
Montfort et al. (2004) demonstrated that the N188S mutant enzyme retains a relatively high level of activity, suggesting that it is probably a very mild mutation or a modifier variant.
In a patient with Gaucher disease type I (230800), Horowitz and Zimran (1994) reported a 4113T-A transversion of the GBA gene leading to a change from phenylalanine to valine at position 216.
In a patient with type I Gaucher disease (230800), Latham et al. (1991) identified a 5259G-T transversion in the GBA gene, resulting in an ala309-to-val (A309V) substitution.
In a patient with type I Gaucher disease (230800), Latham et al. (1991) identified a 5269G-T transversion in the GBA gene, resulting in a trp312-to-cys (W312C) substitution.
In a patient with type II Gaucher disease (230900), Eyal et al. (1990) identified compound heterozygosity for 2 mutations in the GBA gene: a 5306G-A transition, resulting in a gly325-to-arg (G325R) substitution, and C342G (606463.0031).
In a patient with type II Gaucher disease (230900), Eyal et al. (1990) identified compound heterozygosity for 2 mutations in the GBA gene: a 5357T-G transversion, resulting in a cys342-to-gly (C342G) substitution, and G325R (606463.0030).
In a patient with type I Gaucher disease (230800), Latham et al. (1991) identified a 5424G-C transversion in the GBA gene, resulting in a ser364-to-thr (S364T) substitution.
In a Bedouin patient with type I Gaucher disease (230800), Rockah et al. (1997) identified a homozygous 259C-T transition (1763 genomic DNA) in the GBA gene. The patient was 26 years old and had moderate thrombocytopenia and an enlarged spleen and liver, as well as Gaucher cells in a bone marrow biopsy and low levels of glucocerebrosidase activity. The same mutation in compound heterozygous state had been described by Beutler et al. (1995) in a Bedouin patient with type I Gaucher disease; this patient carried a 1448G mutation in addition to the 259T mutation. His phenotype was severe but with no neurologic signs.
In a fetus with perinatal lethal Gaucher disease (608013), Tayebi et al. (1997) identified a homozygous 1-bp deletion in the GBA gene, resulting in a frameshift and premature termination of the protein in exon 6. This 22-week-old fetus, the offspring of a first-cousin marriage, had hydrops, external abnormalities, hepatosplenomegaly, and Gaucher cells in several organs. Western blot analysis confirmed absence of glucocerebrosidase protein.
In 3 sibs with Gaucher disease with neurologic involvement (231000), born of parents related as first cousins once removed, Parenti et al. (1998) identified a 5390C-G transversion in the GBA gene, resulting in an arg353-to-gly (R353G) substitution. The 3 affected sibs were all adults, the youngest being 26 years old. Neurologic signs observed in type III Gaucher disease, such as deficits of the saccadic eye movements, cerebellar abnormalities, or myoclonus, were not present in these 3 sisters. However, the oldest sister had generalized tonic-clonic seizures beginning at the age of 23 years, requiring therapy. The next younger sister with Gaucher disease had partial seizures, and the youngest sister with Gaucher disease had EEG and other electrophysiologic abnormalities indicative of dysfunction of the motor cortex. Since none of these clinical or laboratory findings were present in the sibs without Gaucher disease, Parenti et al. (1998) concluded that the GBA mutation was responsible for the neurologic involvement.
Extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led Wasserstein et al. (1999) to the diagnosis of type I Gaucher disease (230800). The patient had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid beta-glucosidase activity. Mutation analysis showed compound heterozygosity for 2 mutations in the GBA gene: an N370S mutation (606463.0003) and a pro401-to-leu (P401L) substitution in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity, which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype, which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fractures, and tooth loss, Wasserstein et al. (1999) suggested that regular dental assessments in type I Gaucher disease are warranted.
In 2 female sibs with perinatal lethal Gaucher disease (608013), Stone et al. (1999) identified a homozygous mutation in exon 8 of the GBA gene, resulting in a his311-to-arg (H311R) substitution. The older sib was hydropic and delivered dead at 31 weeks' gestation. The second infant was hydropic and delivered alive at 30 weeks' gestation but died shortly after birth. The parents were a consanguineous couple from Cape Verde.
In a male infant with perinatal lethal Gaucher disease (608013), Stone et al. (1999) identified compound heterozygosity for 2 mutations in the GBA gene: a mutation in exon 8 resulting in an arg359-to-ter (R359X) substitution, and a mutation in exon 9 resulting in a val398-to-phe (V398F) substitution (606463.0039). The patient's father was from Surinam and his mother was Dutch.
For discussion of the mutation in exon 9 of the GBA gene, resulting in a val398-to-phe (V398F) substitution, that was found in compound heterozygous state in a male infant with perinatal lethal Gaucher disease (608013) by Stone et al. (1999), see 606463.0038.
In 3 Portuguese patients with type I Gaucher disease (230800), Amaral et al. (1999) identified homozygosity for a gly377-to-ser (G377S) substitution in the GBA gene. All 3 had mild to moderate severity with severity score indices (SSI), as defined by Zimran et al. (1989), of 8, 14, and 10, respectively. One of them had had splenectomy at age 9; the other 2 had recognized onset at ages 39 and 48 years. G377S seems to be common in Iberian patients, representing 7% and 5% of alleles in Portuguese and Spanish patients, respectively, according to Amaral et al. (1999).
Park et al. (2003) identified a heterozygous G377S mutation in patients with type III Gaucher disease (231000); they had additional pathogenic GBA mutations.
For discussion of the arg257-to-glu (R257E) mutation in the GBA gene that was found in compound heterozygous state in a preterm infant with perinatal lethal Gaucher disease (608013) by Stone et al. (2000), see 606463.0023.
In a sib pair with perinatal lethal Gaucher disease (608013), born to Mexican parents, Stone et al. (2000) detected homozygosity for a mutation in the GBA gene resulting in an arg131-to-leu (R131L) substitution. The parents were unaware of any common ancestry, and genetic studies to confirm or refute consanguinity were not possible. The first-born was a male infant with collodion skin at birth which improved within 2 weeks. He subsequently developed rapidly progressive neurologic disease and died at 7 months. Fibroblast glucocerebrosidase activity was 3% of control values. His sister was diagnosed by prenatal enzyme assay and was born at 37 weeks' gestation with collodion skin and hepatosplenomegaly. Her skin condition resolved during the first month of life, but she developed neurologic abnormalities and died at age 9 months.
Zhao et al. (2003) described a 57-year-old woman of Cherokee ancestry with Gaucher disease type I (230800) who was homozygous for a 2855G-C transversion in exon 4 of the GBA gene causing a lys79-to-asn (K79N) substitution. They also described a 2-year-old male of Caucasian/Cherokee ancestry with Gaucher disease type III (231000) who was a compound heterozygote for the same K79N allele and a novel complex mutation (null allele). The K79N allele was identical in the 2 cases as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (Gaucher disease types I and III) in these 2 patients provided support for a threshold of residual activity necessary to 'protect' the CNS from the pathogenic effects of the disease.
In an infant with the perinatal lethal variant of Gaucher disease (608013), Zhao et al. (2003) described compound heterozygosity for 2 mutations in the GBA gene: IVS2+1G-A (606463.0015) and a 5101C-A transversion resulting in a phe251-to-leu (F251L) substitution. Both enzyme activity and protein were greatly decreased in cultured skin fibroblasts. After birth, the patient was noted to have absent respiratory effort, tight shiny skin, a heart murmur, and frequent myoclonic jerks and died at age 1 month due to respiratory failure.
In 6 affected members in 3 generations of a consanguineous Lebanese family with moderately severe type I Gaucher disease (230800), Shamseddine et al. (2004) identified homozygosity for a 1228C-G transversion in the GBA gene, resulting in a leu371-to-val (L371V) mutation. The disorder was more severe than that observed with the common N370S (606463.0003) mutation associated with type I Gaucher disease.
In a premature infant with perinatal lethal Gaucher disease (608013), Felderhoff-Mueser et al. (2004) identified compound heterozygosity for the R120Q mutation (606463.0004) and a G-to-A substitution at the first position in the splice site of intron 10 of the GBA gene, resulting in the insertion of the first 11 basepairs of IVS10 and deletion of the first 11 basepairs of exon 11.
In a 25-month-old girl with an atypical form of neuronopathic Gaucher disease between type II (230900) and type III (231000), Filocamo et al. (2005) identified homozygosity for a complex allele containing 2 GBA mutations in cis: an 882T-G transversion in exon 7 resulting in a his255-to-gln (H255Q) substitution and a 1342G-C transversion in exon 10 resulting in an asp409-to-his (D409H; 606463.0006) substitution. Onset of symptoms occurred at age 5 months with hepatosplenomegaly. A few months later, she developed neurologic features, including spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. At age 25 months, she showed slow symptom progression and was able to sit alone, walk with support, and pronounce some words.
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